Sleep apnea affects up to 20% of the adult population, exposing sufferers to periods of hypoxia/hypercapnia during sleep. Consequences of this condition include significant vascular changes with concomitant hypertension and cardiovascular disease. Sleep apnea patients have elevated circulating endothelin-1 (ET-1) which may contribute to the hypertension and we have previously demonstrated that exposing rats to intermittent hypoxia/hypercapnia (IH/HC) during sleep to mimic sleep apnea causes sustained, ET-1-dependent systemic hypertension. New preliminary data demonstrate that mesenteric resistance arteries from these hypertensive IH rats have augmented vasoconstrictor responses to ET-1 but not to phenylephrine or KCI. Intriguingly, augmented ET-1 constriction in IH/HC arteries appears to be mediated entirely by increases Ca2+ sensitivity while ET constriction in Sham arteries is mediated by increases in both [Ca2+]i and Ca2+ sensitivity. Furthermore, ET-1 appears to activate PKC in IH/HC but not Sham arteries, a pathway shown to increase arterial Ca2+ sensitivity. Therefore, we hypothesize that augmented ET-1-mediated vasoconstriction in arteries from rats made hypertensive with IH/HC is caused by increased activation of PKC signaling. Three aims will test this hypothesis: Aim 1) Determine PKC isoform expression, activity and agonist-dependent activation in small mesenteric arteries from Sham and IH/HC treated rats. Aim 2) Determine the relative contributions of PKC and ROK to ET-1 and PE activation of Ca2+- sensitization in mesenteric arteries from IH/HC and Sham-treated rats. Aim 3) Determine the effect of IH/HC on basal and agonist stimulated synthesis and degradation of PKC activator, diacylglycerol (DAG) in arteries from Sham and IH/HC rats. Planned studies will determine the role of PKC-dependent Ca-sensitization in augmented ET-1 dependent vasoconstriction in this rat model of sleep apnea. These studies should fundamentally advance our understanding of ET-1 and PKC signaling in vascular smooth muscle and the cardiovascular consequences of chronic exposure to sleep apnea. The anticipated findings are expected to provide a mechanistic explanation for in vivo observations that ET-1 contributes to vascular dysfunction in sleep apnea and other disease states, sometimes when circulating levels of the peptide are not elevated.